Cogent Biosciences has submitted an NDA for bezuclastinib in advanced systemic mastocytosis (AdvSM), completing a trio of FDA filings for the KIT D816V inhibitor across three indications within six months. Supported by pivotal APEX trial data, the filing positions bezuclastinib as a potential challenger to the current treatment standard in AdvSM while giving Cogent three simultaneous FDA reviews for the same asset across advanced systemic mastocytosis, non-advanced systemic mastocytosis (NonAdvSM), and gastrointestinal stromal tumors (GIST).
AdvSM comprises aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia, all of which carry substantially poorer prognoses than non-advanced disease. The NDA is supported by data from the pivotal APEX trial, which enrolled 81 patients treated with bezuclastinib 150 mg.
Among 68 evaluable patients assessed using modified International Working Group–Myeloproliferative Research and Treatment–European Competence Network on Mastocytosis (mIWG-MRT-ECNM) criteria, bezuclastinib achieved a 65% overall response rate, with 57% of patients attaining complete remission, complete remission with partial hematologic recovery, or partial remission. Using pure pathological response criteria across all 81 treated patients, overall response reached 81%.
The responses were accompanied by encouraging durability. Twelve-month progression-free survival was 79% and overall survival was 87%, with median values for both endpoints not yet reached. Biomarker improvements were similarly pronounced, with approximately 90% of patients achieving at least a 50% reduction in serum tryptase, bone marrow mast cell burden, or KIT D816V variant allele frequency. Around one-third of patients achieved undetectable KIT D816V, suggesting deep molecular responses.
Safety findings were consistent with previous experience. The most common treatment-related adverse events were hair color changes, neutropenia, dysgeusia, thrombocytopenia, and transient ALT/AST elevations. Liver enzyme elevations were generally low grade, asymptomatic, and reversible, with treatment discontinuations due to adverse events reported infrequently.